The overall goal of this research project is to determine the mechanism by which activation of the aryl hydrocarbon receptor (AhR) protects against pulmonary infection with Streptococcus pneumoniae. S pneumoniae is a common pathogen that is a significant cause of human disease, including pneumonia, meningitis, and otitis media. The basis for this project is a recent novel discovery that we have made. Specifically, when mice were treated with TCDD (2,3,7,8- tetrachlorodibenzo-p-dioxin), a high-affinity ligand for the AhR, they were highly resistant to an otherwise lethal infection with these bacteria. We believe that this resistance is the result of enhanced activity of cells of the innate immune system, which respond very rapidly to the presence of bacteria in the lung. The hypothesis for the proposed studies is that AhR activation enhances the response of innate immune cells in lung in the immediate hours following infection. These innate immune cells include macrophages and neutrophils, as well as cells that are less well-characterized, namely B-1a B cells and iNKT cells. The rationale for this hypothesis is that the reduced pulmonary bacterial burden in the TCDD-treated mice is evident within 24 hours post-infection, and does not stem from a direct toxic effect of TCDD on the bacteria. Nor does it result from a response of pulmonary epithelial cells to increase production of bactericidal proteins or decrease their provision of binding sites for the bacteria. We will test our hypothesis in the context of three specific aims. In Aim 1, we will identify effects of AhR activation on uptake and killing of S. pneumoniae by pulmonary phagocytes. To accomplish this we will test phagocytosis and bactericidal activity of macrophages and neutrophils in the lung. In Aim 2: we will determine the contribution of natural antibodies and B-1a B cells to the observed host-protection. To accomplish this, we will measure the effect of AhR activation on levels of these cells and antibodies in the pleural cavity and other relevant locations. And in Aim 3, we will determine the effects of AhR activation on iNKT cells. To accomplish this we will examine the recruitment of these cells to the infected lungs and measure the effect of TCDD on their activity in the early hours post infection. Significance: Understanding the mechanism of the protection conferred by AhR activation will provide new insight into the role of the AhR in biological systems, and aid in the development of therapeutic strategies to control or prevent diseases resulting from S. pneumoniae infection. PUBLIC HEALTH RELEVANCE: Streptococcus pneumoniae is a common human pathogen that causes numerous diseases including pneumonia, ear infection, and meningitis. We have recently found that treatment with a compound that activates a cellular receptor is protective against infection with these bacteria. It is our goal to understand the mechanism of this protection, in hopes that this information can be used to improve current therapies for pneumococcal diseases.